I. Field of the Invention
The present invention relates generally to the fields of biology, chemistry, and medicine. More particularly, it concerns compounds, compositions and methods for the treatment and prevention of diseases such as cancer and other proliferative diseases.
II. Description of Related Art
The 90 kDa heat shock protein (Hsp90) is a highly conserved molecular chaperone that plays a pivotal role in the maintenance of protein homeostasis and sustains cell viability during cellular stress (Taipale, et al., 2010). Abnormal expression of Hsp90 has been implicated in a variety of disease states. In cancer, elevated Hsp90 levels are critical for the stabilization and function of oncogenic proteins distributed amongst all six hallmarks of cancer (Hanahan and Weinberg, 2011). Malignant or mutated oncogenic proteins, such as Her-2, Raf-1, Akt, CDK4, Src, Flt-3, hTert, c-Met, etc, are distributed amongst all six hallmarks of cancer and are highly dependent upon the Hsp90 protein folding machinery for their ability to promote cell survival, proliferation, and adaptation (Hanahan and Weinberg, 2011). Therefore, small molecules that inhibit the Hsp90 folding machinery can simultaneously attack multiple signaling pathways that are essential for cancer cell survival, adaptation, proliferation, and provides a unique opportunity for development of cancer therapeutics (Blagg and Kerr, 2006). In such scenarios, Hsp90 inhibition has been implicated in the simultaneous disruption of multiple oncogenic pathways and eventually leads to cancer cell death, while largely sparing normal cells.
Several small molecules that inhibit the N-terminus Hsp90 function are currently in clinical trials for the treatment of various cancers in order to demonstrate the viability of this treatment paradigm (Neckers and Workman, 2012). Unfortunately, small molecules that target the Hsp90 N-terminus have been reported to lead to the concomitant heat shock response induced upon administration of such agents compromises their efficacy and allows cancer cell survival, which may lead to resistance and metastasis (Whitesell, et al., 2012). Further studies have demonstrated the existence of a second nucleotide-binding site at the Hsp90 C-terminus and these small molecules have been shown to bind this region and induce a dose-dependent degradation of Hsp90 client proteins in a manner similar to Hsp90 N-terminal inhibitors (Marcu, et al., 2000). In contrast to N-terminal inhibitors, C-terminal inhibitors have been shown not to induce the pro-survival heat shock response, and these compounds therefore provide an alternative model for Hsp90 modulation (Eskew, et al., 2011; Shelton, et al., 2009; and Conde, et al., 2009). Because the Hsp90 C-terminus is responsible for mediating the interactions with co-chaperones such as HOP (Hsp70-Hsp90 organization protein) and the immunophilins (e.g., FK506 binding protein) to facilitate client protein maturation (Cox and Johnson, 2011, Robson and James, 2012), small molecule modulation of this region exhibits activities not observed with N-terminal inhibitors (Eskew, et al., 2011, Zhang, et al., 2012). Novobiocin was identified as the first Hsp90 C-terminal inhibitor in 2000; albeit with low efficiency (˜700 μM in SKBr3 cells) (Marcu, et al., 2000). Subsequent modification to novobiocin has led to the elucidation of structure-activity relationships and analogues that exhibit superior inhibitory activity (Yu, et al., 2005; Burlison, et al., 2008; Zhao, et al., 2011; Donnelly, et al., 2010; Zhao, et al., 2011). Deletion of both the 4-hydroxy substituent on the coumarin ring and the 3′-carbamoyl group on noviose resulted in DHN2, which transformed novobiocin from a DNA gyrase inhibitor to a selective Hsp90 inhibitor (FIG. 1) (Burlison, et al., 2006). Subsequent replacement of the synthetically complex noviose sugar with readily available amines led to molecules that manifested increased anti-proliferative activity and solubility (FIG. 1, NA-1 and NA-2) (Zhao, et al., 2011). Further improvements on coumarin core to produce other Hsp90 C-terminal inhibitors are of commercial interest.